Synthesis and Anti‐herpetic Activity of Phosphoramidate ProTides

Among the many prodrug approaches aimed at delivering nucleoside monophosphates into cells, the phosphoramidate ProTide approach is one that has shown success, which has made it possible for some of the phosphoramidates to enter into clinical trials. Herein, we report the synthesis and antiviral activity of a series of phosphoramidate ProTides designed to bypass the thymidine kinase (TK) dependence of the parent nucleoside analogues. Phosphoramidate derivatives of (E)‐5‐(2‐bromovinyl)‐2′‐deoxyuridine (BVDU) that contain L ‐alanine or pivaloyloxymethyl iminodiacetate (IDA‐POM) exhibit anti‐HSV‐1 and anti‐VZV activity in cell cultures, but they largely lost antiviral potency against TK‐deficient virus strains. Among deazapurine nucleosides and their phosphoramidate derivatives, the 7‐deazaadenine containing nucleosides and their phosphoramidate triester derivatives showed weak antiviral activity against VZV. Apparently, intracellular nucleotide delivery with these phosphoramidates is partly successful. However, none of the compound prodrugs showed superior activity to their parent drugs.     

co2驱提高采收率技术研究进展

随着一些油田开发进入后期,注水开发以及一些三次采油技术已经不能再提高采收率,这时CO2驱作为一项提高原油采收率的技术在现场得到了广泛应用。目前,此项技术在美国、加拿大等国的应用已较成熟。我国对该技术的研究相对较晚,对该工艺还需要深入研究。在国内,随着CO2气源的发现,此项技术正在被越来越多的油田应用。本文在调研国内外大量文献资料的基础上,阐明了CO2提高原油采收率的机理,注水方式以及CO2驱提高采收率的研究现状及进展,并总结了适合CO2驱目标储层的筛选标准。     

Allosteric inhibitor development targeting HIV-1 integrase

HIV-1 integrase (IN) is one of three essential enzymes for viral replication, and is a focus of ardent antiretroviral drug discovery and development efforts. Diligent research has led to the development of the strand-transfer-specific chemical class of IN inhibitors, with two compounds from this group, raltegravir and elvitegravir, advancing the farthest in the US Food and Drug Administration (FDA) approval process for any IN inhibitor discovered thus far. Raltegravir, developed by Merck & Co., has been approved by the FDA for HIV-1 therapy, whereas elvitegravir, developed by Gilead Sciences and Japan Tobacco, has reached phase?III clinical trials. Although this is an undoubted success for the HIV-1 IN drug discovery field, the emergence of HIV-1 IN strand-transfer-specific drug-resistant viral strains upon clinical use of these compounds is expected. Furthermore, the problem of strand-transfer-specific IN drug resistance will be exacerbated by the development of cross-resistant viral strains due to an overlapping binding orientation at the IN active site and an equivalent inhibitory mechanism for the two compounds. This inevitability will result in no available IN-targeted therapeutic options for HIV-1 treatment-experienced patients. The development of allosterically targeted IN inhibitors presents an extremely advantageous approach for the discovery of compounds effective against IN strand-transfer drug-resistant viral strains, and would likely show synergy with all available FDA-approved antiretroviral HIV-1 therapeutics, including the IN strand-transfer-specific compounds. Herein we review the concept of allosteric IN inhibition, and the small molecules that have been investigated to bind non-active-site regions to inhibit IN function.     

iPSCs: A Preclinical Drug Research Tool for Neurological Disorders

The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval for therapeutic use. Preclinical studies are usually performed using both cell cultures and animal models, although they do not completely resume the complexity of human diseases, in particular neurodegenerative conditions. To this regard, stem cells represent a powerful tool in all steps of drug discovery. The recent advancement in induced Pluripotent Stem Cells (iPSCs) technology has opened the possibility to obtain patient-specific disease models for drug screening and development. Here, we report the use of iPSCs as a disease model for drug development in the contest of neurological disorders, including Alzheimer’s (AD) and Parkinson’s disease (PD), Amyotrophic lateral Sclerosis (ALS), and Fragile X syndrome (FRAX).     

填料对厌氧氨氧化反应器启动过程的影响探讨

厌氧氨氧化工艺是当今废水生物脱氮领域的重大发现,具有非常高的研究和开发价值。由于厌氧氨氧化反应器启动过程非常缓慢,极大的限制了其工程化应用的进程。本文通过分析各种类型反应器的特点,探讨了不同类型的填料对厌氧氨氧化反应器启动过程的影响,为该技术的实际应用奠定了基础。     

A Case Study of Single‐Pill Combination Therapy: The Ezetimibe/Simvastatin Combination for Treatment of Hyperlipidemia

In recent years, combination therapy has received growing popularity as a powerful therapeutic tactic for the treatment of diseases. The justifications and benefits of combination therapy are far‐reaching, including but not limited to addressing unmet medical needs such as cancer, malaria, and HIV/AIDS, improved clinical efficacy and safety with reduced dosage of a single medication, understanding the underlying science of the disease, alleviating pharmaco‐economic impacts, and better drug life‐cycle management. Using the ezetimibe/simvastatin combination therapy as a case study, a comprehensive overview of the successful discovery and development of the single‐pill combination, Vytorin, is presented in this review. A cursory introduction to combination therapy and the rationale for the ezetimibe/simvastatin combination for the treatment of hyperlipidemia provides an instructive entry point. The discovery and mode of action of simvastatin and ezetimibe monotherapies set the scene for a detailed discussion on the discovery and development of Vytorin, with emphasis on bioequivalency studies, clinical efficacy and safety profile studies, and the economic consequences of the single‐pill combination therapy. Large‐scale outcome clinical trials are also discussed to demonstrate the long‐term effects of Vytorin.     

单核苷酸多态性研究进展

作为第三代DNA遗传标记,单核苷酸多态性(SNP)标记在发现相关基因突变方面发挥了重大作用,近年来发现SNP与药物或疾病的易感性有显著的相关性.综述了SNP的研究现状.     

The pharmaceutical biochemistry group: where pharmaceutical chemistry meets biology and drug delivery

Successful drug discovery and development of new therapeutics is a long, expensive multidisciplinary process needing innovation and the integration of smart cutting edge science and technology to overcome the challenges in taking a drug from the bench to the bedside. The research activities of the Pharmaceutical Biochemistry group span the drug discovery and development process, providing an interface that brings together pharmaceutical chemistry, biochemistry, structural biology, computational chemistry and biopharmaceutics. Formulation and drug delivery are brought into play at an earlier stage when facing the perennial challenge of transforming a potent molecule in vitro into a therapeutic agent in vivo. Concomitantly, drug delivery results can be understood at a molecular level. This broad range of interdisciplinary research activities and competences enables us to address key challenges in modern drug discovery and development, provides a powerful collaborative platform for other universities and the pharmaceutical industry and an excellent training platform for pharmacists and pharmaceutical scientists who will later be involved in drug discovery and development.     

Exploring RNA structural codes with SHAPE chemistry

RNA is the central conduit for gene expression. This role depends on an ability to encode information at two levels: in its linear sequence and in the complex structures RNA can form by folding back on itself. Understanding the global structure-function interrelationships mediated by RNA remains a great challenge in molecular and structural biology. In this Account, we discuss evolving work in our laboratory focused on creating facile, generic, quantitative, accurate, and highly informative approaches for understanding RNA structure in biologically important environments. The core innovation derives from our discovery that the nucleophilic reactivity of the ribose 2'-hydroxyl in RNA is gated by local nucleotide flexibility. The 2'-hydroxyl is reactive at conformationally flexible positions but is unreactive at nucleotides constrained by base pairing. Sites of modification in RNA can be detected efficiently either using primer extension or by protection from exoribonucleolytic degradation. This technology is now called SHAPE, for selective 2'-hydroxyl acylation analyzed by primer extension (or protection from exoribonuclease). SHAPE reactivities are largely independent of nucleotide identity but correlate closely with model-free measurements of molecular order. The simple SHAPE reaction is thus a robust, nucleotide-resolution, biophysical measurement of RNA structure. SHAPE can be used to provide an experimental correction to RNA folding algorithms and, in favorable cases, yield kilobase-scale secondary structure predictions with high accuracies. SHAPE chemistry is based on very simple reactive carbonyl centers that can be varied to yield slow- and fast-reacting reagents. Differential SHAPE reactivities can be used to detect specific RNA positions with slow local nucleotide dynamics. These positions, which are often in the C2'-endo conformation, have the potential to function as molecular timers that regulate RNA folding and function. In addition, fast-reacting SHAPE reagents can be used to visualize RNA structural biogenesis and RNA-protein assembly reactions in one second snapshots in very straightforward experiments. The application of SHAPE to challenging problems in biology has revealed surprises in well-studied systems. New regions have been identified that are likely to have critical functional roles on the basis of their high levels of RNA structure. For example, SHAPE analysis of large RNAs, such as authentic viral RNA genomes, suggests that RNA structure organizes regulatory motifs and regulates splicing, protein folding, genome recombination, and ribonucleoprotein assembly. SHAPE has also revealed limitations to the hierarchical model for RNA folding. Continued development and application of SHAPE technologies will advance our understanding of the many ways in which the genetic code is expressed through the underlying structure of RNA.     

Fragment-Based Screening by Protein Crystallography: Successes and Pitfalls

Fragment-based drug discovery (FBDD) concerns the screening of low-molecular weight compounds against macromolecular targets of clinical relevance. These compounds act as starting points for the development of drugs. FBDD has evolved and grown in popularity over the past 15 years. In this paper, the rationale and technology behind the use of X-ray crystallography in fragment based screening (FBS) will be described, including fragment library design and use of synchrotron radiation and robotics for high-throughput X-ray data collection. Some recent uses of crystallography in FBS will be described in detail, including interrogation of the drug targets β-secretase, phenylethanolamine N-methyltransferase, phosphodiesterase 4A and Hsp90. These examples provide illustrations of projects where crystallography is straightforward or difficult, and where other screening methods can help overcome the limitations of crystallography necessitated by diffraction quality.     

溶胶-凝胶的制备及其在化学修饰电极中的应用

溶胶-凝胶技术的进一步改善和一些新材料的发现,为固定生物分子制备具有更好的响应性能的化学修饰电极提供了更多的机会和更大空间。追溯了溶胶-凝胶的起源,介绍了溶胶-凝胶制备的方法,综述了溶胶-凝胶在构筑化学修饰电极中的作用,展望了溶胶-凝胶技术应用的发展趋势。     

Ligand-based vascular targeting of disease

This review illustrates the basic principles of ligand-based vascular targeting and presents some of the most advanced results obtained in this field, not only in terms of biopharmaceuticals, which are currently being investigated in clinical and preclinical studies, but also in terms of enabling technologies that facilitate target and ligand discovery. Whereas most of the vascular targeting research activities have so far concentrated on tumoral angiogenesis, the development of non-oncological applications has recently gained momentum and is likely to become an important area of modern pharmaceutical research.     

Recent Development of Benzimidazole‐Containing Antibacterial Agents

Clinically significant antibiotic resistance is one of the greatest challenges of the twenty‐first century. However, new antibacterial agents are currently being developed at a much slower pace than our growing need for such drugs. Given their diverse biological activities and clinical applications, many bioactive heterocyclic compounds containing a benzimidazole nucleus have been the focus of interest for many researchers. The benzimidazole nucleus is a structural isostere of naturally occurring nucleotides. This advantage allows benzimidazoles to readily interact with the various biopolymers found in living systems. In view of this situation, much attention has been given to the exploration of benzimidazole‐based antibacterial agents, leading to the discovery of many new chemical entities with intriguing profiles. In this minireview we summarize novel benzimidazole derivatives active against various bacterial strains. In particular, we outline the relationship between the structures of variously modified benzimidazoles and their antibacterial activity.     

Computational Chemistry in the Pharmaceutical Industry: From Childhood to Adolescence

Computational chemistry within the pharmaceutical industry has grown into a field that proactively contributes to many aspects of drug design, including target selection and lead identification and optimization. While methodological advancements have been key to this development, organizational developments have been crucial to our success as well. In particular, the interaction between computational and medicinal chemistry and the integration of computational chemistry into the entire drug discovery process have been invaluable. Over the past ten years we have shaped and developed a highly efficient computational chemistry group for small‐molecule drug discovery at Bayer HealthCare that has significantly impacted the clinical development pipeline. In this article we describe the setup and tasks of the computational group and discuss external collaborations. We explain what we have found to be the most valuable and productive methods and discuss future directions for computational chemistry method development. We share this information with the hope of igniting interesting discussions around this topic.     

Track-Etched Membranes for Drug Pharmaceutical Research

Over the last decades, the incorporation of membranes into micro physiological systems used for pharmaceutical research and drug development has grown significantly. One example is the use of microporous track-etched membranes in microfluidic systems like organs-on-a-chip and cell culture inserts for tissue engineering. Tissue-culture treated track-etched membranes serve as excellent support for cell growth and efficient nutrient supply, with the added benefit of precise control of pore parameters, a critical pre-requisite to achieve reproducible results. Here, we provide an overview of track-etched membrane technology in the context of applications in drug discovery and development.     

蛋白质芯片技术的研究及前景

蛋白质芯片技术是近年发展起来的一项生物检测技术,这项技术是将蛋白质的分析微缩到小型芯片上进行,利用荧光或酶显色进行探测,最后用特定的计算机软件加以分析。该技术在对基因表达、抗原抗体检测、药物开发、疾病诊断等研究方面显示出快速、高效、高通量处理信息的能力。本文简要综述了该技术的基本原理及在基础研究和疾病诊断中的初步应用和发展前景。     

Role of MicroRNA-7 (MiR-7) in Cancer Physiopathology

miRNAs are non-coding RNA sequences of approximately 22 nucleotides that interact with genes by inhibiting their translation through binding to their 3′ or 5′ UTR regions. Following their discovery, the role they play in the development of various pathologies, particularly cancer, has been studied. In this context, miR-7 is described as an important factor in the development of cancer because of its role as a tumor suppressor, regulating a large number of genes involved in the development and progression of cancer. Recent data support the function of miR-7 as a prognostic biomarker in cancer, and miR-7 has been proposed as a strategy in cancer therapy. In this work, the role of miR-7 in various types of cancer is reviewed, illustrating its regulation, direct targets, and effects, as well as its possible relationship to the clinical outcome of cancer patients.     

抗氧化天然活性多糖

化妆品市场是个充分竞争的市场,也是个同质化比较严重的市场。如何开发化妆品的天然特质,通过对新科技的探索发现,多糖作为一类重要的天然活性高分子,以其独特的抗氧化生物活性,广泛应用于化妆品领域。结合中国本土特色的动植物资源的开发研究,简要介绍了其作用机理以及几种具有应用于化妆品领域潜力的天然活性多糖。